Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model.
ABSTRACT The Wnt/β-catenin pathway plays a key role in liver development, regeneration and tumorigenesis. Among human cancers tightly linked to abnormal Wnt/β-catenin signaling, hepatoblastoma (HB) presents with the highest rate (50-90%) of β-catenin mutations. HB is the most common malignant tumor of the liver in childhood. This embryonic tumor differs from hepatocellular carcinoma by the absence of viral etiology and underlying liver disease, and by distinctive morphological patterns evoking hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes. Recent studies of the molecular pathogenesis of hepatoblastoma have led to identify two major tumor subclasses resembling early and late phases of prenatal liver development and presenting distinctive chromosomal alterations. It has been shown that the molecular signature of Wnt/β-catenin signaling in hepatoblastoma is mainly imposed by liver context, but differs according to developmental stage. Finally, the differentiation stage of tumor cells strongly influences their invasive and metastatic properties, therefore affecting clinical behavior.
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ABSTRACT: Beta-catenin, the central component of the canonical Wnt pathway, plays important roles in the processes of liver regeneration, growth, and cancer. Previously, we identified temporal expression of beta-catenin during liver development. Here, we characterize the hepatic phenotype, resulting from the successful deletion of beta-catenin in the developing hepatoblasts utilizing Foxa3-cyclization recombination and floxed-beta-catenin (exons 2 through 6) transgenic mice. Beta-catenin loss in developing livers resulted in significantly underdeveloped livers after embryonic day 12 (E12) with lethality occurring at around E17 stages. Histology revealed an overall deficient hepatocyte compartment due to (1) increased cell death due to oxidative stress and apoptosis, and (2) diminished expansion secondary to decreased cyclin-D1 and impaired proliferation. Also, the remnant hepatocytes demonstrated an immature phenotype as indicated by high nuclear to cytoplasmic ratio, poor cell polarity, absent glycogen, and decreased expression of key liver-enriched transcription factors: CCAAT-enhancer binding protein-alpha and hepatocyte nuclear factor-4alpha. A paucity of primitive bile ducts was also observed. While the stem cell assays demonstrated no intrinsic defect in hematopoiesis, distorted hepatic architecture and deficient hepatocyte compartments resulted in defective endothelial cell organization leading to overall fetal pallor. CONCLUSION: Beta-catenin regulates multiple, critical events during the process of hepatic morphogenesis, including hepatoblast maturation, expansion, and survival, making it indispensable to survival.Hepatology 06/2008; 47(5):1667-79. · 12.00 Impact Factor
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ABSTRACT: During hepatogenesis, after the liver has budded out of the endoderm, the hepatoblasts quickly expand and differentiate into either hepatocytes or biliary cells, the latter of which arise only within the ductal plate surrounding the portal vein. Because the Wnt/beta-catenin pathway is involved in liver homeostasis and regeneration and in liver carcinogenesis, we investigated here a role for Wnt/beta-catenin signaling in the embryonic liver. A cyclization recombination (Cre)/locus of X-over P1 (loxP) strategy was chosen to perform adenomatous polyposis coli (Apc) invalidation in order to activate ectopic beta-catenin signaling in hepatoblasts; an appropriate transgenic model expressing the Cre recombinase was used. Phenotypic and immunolocalization studies, together with messenger RNA analyses, by microarray and real-time quantitative polymerase chain reaction approaches were performed on this model during normal hepatogenesis. The loss of Apc allowed beta-catenin activation in the hepatoblasts after the formation of the liver bud and led to embryonic lethality. In this model, the liver became hypoplastic, and hepatocyte differentiation failed, whereas beta-catenin-activated ducts developed and gave rise to fully differentiated bile ducts when transplanted into adult recipient livers. Microarray analyses suggested that beta-catenin plays a role in repressing the hepatocyte genetic program and remodeling the ductal plate. According to these data, in normal embryonic livers, beta-catenin was transiently activated in the nascent bile ducts. Conclusion: We demonstrated a key role for the Wnt/beta-catenin pathway in liver embryonic growth and in controlling the fate of hepatoblasts, preventing them from differentiating toward the hepatocyte lineage, and guiding them to biliary ductal morphogenesis.Hepatology 02/2008; 47(1):247-58. · 12.00 Impact Factor
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ABSTRACT: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common primary liver cancers in children. Recent advances in management of pediatric liver cancer have improved disease-specific survival (DSS). This is a review of our experience with childhood liver malignancy over the past 3 decades. A retrospective chart review from 1975 to 2005 identified patients who were 18 years old or younger with a histologically confirmed diagnosis of primary liver cancer. Patients were staged according to the Children's Cancer Group and Pediatric Oncology Group (CCG/POG) system. Patients were followed up prospectively through clinic visits and mail correspondence. Standard statistical methods were used for comparison, risk, and survival analyses. Fifty-two patients were confirmed to have primary liver cancers, where 24 (46%) patients had HB, 22 (42%) had HCC, 3 (6%) had sarcomas, and 3 (6%) had other histologies. Mean ages at presentation for HB and HCC were 3.2 and 13.1 years old, respectively. The most common presentations were abdominal mass (67%) and pain (40%). Most patients underwent major liver resection (n = 45, 87%), including: lobectomy (n = 25, 48%), and trisegmentectomy (n = 11, 21%). Three patients underwent liver transplantation (n = 3, 6%) for advanced local disease. Forty-five (87%) received primary or neoadjuvant and/or adjuvant chemotherapy. Patients had the following CCG/POG stages: I (n = 31, 60%), II (n = 6, 11.5%), III (n = 9, 17%), and IV (n = 6, 11.5%). Complete gross resection (stage I and II) was achieved in 37 (71%) patients. The perioperative mortality and morbidity rates were 0% and 29%, respectively. Patients with complete resection had significantly better 5-year DSS and median survival compared with incomplete gross resection: 62% vs 9% and 216 vs 18 months, P < .001. Patients treated during the period 1995-2005 had better 5-year DSS and median survival compared with those treated during 1975-1994: 68% vs 32% and 117 vs 27 months, P = .032. All 3 patients who underwent transplantation for conventionally unresectable disease are alive without disease recurrence (follow-up period, 1-15 years). Complete resection of the pediatric primary liver tumors remains the cornerstone of treatment to achieve cure. Major liver resection can be performed with minimal perioperative mortality and morbidity. Patients with HB appeared to have better survival compared with patients with HCC, and there was significant improvement in the DSS of children treated in the recent decade. Liver transplantation in conjunction with chemotherapy may have an increasing role in the management of locally advanced primary liver cancers.Journal of Pediatric Surgery 05/2007; 42(5):834-9. · 1.38 Impact Factor